Multiple Myeloma Course with Renal Insufficiency in Young Patient: Case Report

Introduction: Multiple myeloma (MM) is a malignant neoplasm characterized by the clonal proliferation of abnormal plasma cells in the bone marrow (OM). The average age of patients diagnosed with MM is approximately 70 years, being relatively uncommon in younger individuals. Objective: To report a case of a young patient with multiple myeloma. Case Description: A 42-year-old male patient presented with continuous and progressive low back pain for 3 months, associated with adynamia, weight loss (10 kg), episodes of constipation and bleeding in the oral cavity in this period. Examinations at the first appointment revealed moderate anemia (Hb 7.4 g / dL), leukocytosis, thrombocytopenia, hypercalcemia, and altered renal function (Cr 5.9 and Ur 178), chest tomography indicating vertebral fracture in T6, T11, L2 and L4. Referred for specialized follow-up, he performed electrophoresis of serum proteins with the presence of a monoclonal peak in the gamma globulin fraction. The immunofixation test confirmed monoclonality for IgA isotype and Kappa light chain (IgA / Kappa). The myelogram showed plasmacytosis of more than 50% of mononuclear cells in the bone marrow. He developed renal failure (with dosage of creatinine of 10.1 mg/ dL. and urea of 208 mg/dL) and hypercalcemia requiring dialysis therapy on the third day of hospitalization, having undergone chemotherapy with Bortezomib, cyclophosphamide and dexamethasone. During this period, infection by the multisensitive S. aureus in catheter occurred and, despite being treated with specific antibiotic therapy, it evolved with clinical worsening and hemodynamic instability and was referred to the Intensive Care Unit, going to death after 2 days. Conclusion: Young patients with MM may study with more aggressive characteristics. Despite the use of new therapeutic agents, more effective treatment strategies need to be studied more for patients in this age group. Disclosures No relevant conflicts of interest to declare.

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A Fully Automated Method for Isolating Highly Enriched Population of Multiple Myeloma Plasma Cell From Whole Bone Marrow for Enhanced Sensitivity in Downstream Assays

Blood ◽

10.1182/blood.v118.21.5064.5064 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5064-5064

Author(s):

Hossein Mossafa ◽

Sabine Defasque ◽

Hamid Belaouni ◽

Adrian Arechiga

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Dna Extraction ◽

Mononuclear Cells ◽

Plasma Cells ◽

Conflicts Of Interest ◽

Snp Array ◽

Fish Analysis ◽

Automated Method

Abstract Abstract 5064 Introduction, Multiple myeloma (MM) is characterized by a huge clinical heterogeneity despite the homogenous morphologic appearance of malignant plasma cells (PCs). The advent of interphase fluorescence in situ hybridization (FISH) or MicroArrays (MA) allows an increased rate of aberration detection and identification of some recurrent cryptic changes, which have been increasingly implemented as additional diagnostic and prognostic factors. To heighten sensitivity of Single Nucleotide Polymorphism (SNP) arrays, or FISH it is necessary to have a purified population of cells as starting material. Screening must be performed systematically on the purified CD138+ PCs. After testing different systems for cell purification, we encountered some challenges. We didn't obtain enough PCs for FISH and SNP array studies. This was due to excess M-protein accumulating in the blood stream, increasing hyper viscosity and also due to the morphology and size variations of PCs at various stages of differentiation. Additionally, downstream DNA extraction can be a challenge since EDTA found in most buffers is an inhibitor for chemical PCR reaction for some MA chips. Given the challenges, CERBA laboratory and Miltenyi Biotec GmbH have developed a fully automated process (FAP) for purification for CD138+ PCs. In a study of 100 BM patient samples, we compared the specificity, efficiency, performance, purity, ease of use, technologists' time and the quality of DNA after CD138+ PCs purification. Two methods were compared. In the first method, cells were directly purified from bone marrow samples by FAP using Automated Magnetic Cell Sorter (AMCS). In the second method, mononuclear cells from fresh whole bone marrow (WBM) were enriched by Ficoll, followed by cell selection procedure with anti-CD138+ MicroBeads using the AutoMACS®. Before separation and following the separation, the percentage of PCs was determined by Flow cytometry (FC) on WBM by multiparameter FC (MFC) for CD138/CD38 expression. Additionally, DNA quality on separated cells was assessed by Nanodrop. A fraction of the CD138+ PCs were used after hypotonic shock and Carnoy fixation, applied to glass slides for FISH application and another fraction for DNA extraction for MA (SNP.6 Affymetrix®) FISH was performed with the recommended unbalanced alterations & reciprocal rearrangements: del(13) (q14)(D13S25), del(17)(p13)(TP53),+3(D3Z), +9(D9Z1), +15(D15Z14), t(4;14)(p16;q32)/IGH-FGFR3. Results, the specificity and purity were the same for both process but the efficiency and performance were considerably better for FAP than mononuclear cells enriched by Ficoll (MCEFicoll) process. With FAP, in 95% of the MM cases we obtained enough PCs for performance of the recommended panel of FISH and for 50% of them we could extract DNA for SNP array. For the MCEFicoll, we observed inferior performance, with very few plasma cells after isolation. Having enough PSc for only 65% of the cases and we could only extract DNA for 28% of them. The quality of DNA was the same for both process and the technologists' time was longer by 30' /patient for MCEFicoll process than for FAP. Currently in CERBA lab, we realize more than 20 plasma cells isolation per week for patients with MM and from October 2007 to July 2011 we have separated more than 5.000 specimens using CD138 Whole Blood MicroBeads (CD 138 WBMB) from Miltenyi Biotec, in combination with the AMCS. This has allowed isolation directly from WBM without any sample preparation required, such as density gradient centrifugation (ficoll) or erythrocyte lysis. The detection rate of chromosomal abnormalities and the number of abnormalities per case in MM and PCs dyscrasia significantly improves when there are enough CD138+PCs for analysis. Conclusion, in this report we describe the benefits of fully automated isolations of CD138+ cells from WBM. We have developed an SOP for an automated reliable and standardized method which allows the processing of multiple samples in a single day, while maintaining sample integrity and increasing sensitivity of FISH analysis and WG arrays for a diagnosis lab. Disclosures: No relevant conflicts of interest to declare.

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Expression and Clinical Significance of Notch1 On the Membrane of Bone Marrow CD38+CD138+Plasma Cells in the Patients with Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.4981.4981 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4981-4981

Author(s):

Rong Fu ◽

Yiran Zhao ◽

Zonghong Shao ◽

Honglei Wang ◽

Tian Zhang ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Lactate Dehydrogenase ◽

Serum Level ◽

Mononuclear Cells ◽

Plasma Cells ◽

Conflicts Of Interest ◽

Newly Diagnosed ◽

Term Outcome ◽

Long Term Outcome

Abstract Abstract 4981 Objective: To investigate the expression of bone marrow CD38+CD138+, CD38+CD138-plasma cells and the expression of Notch1 on the membrane of them in the patients with multiple myeloma(MM), and explore the importance of Notch signaling pathway in the formation and progression of MM further. Methods: Thirty-three MM patients and 15 healthy controls were enrolled in this study. The expression of bone marrow CD38+CD138+, CD38+CD138-plasma cells and the expression of Notch1 on the membrane of them were analyzed by flow cytometry. The expression of Notch1 mRNA of bone marrow mononuclear cells were analyzed by RT-PCR. Results: The ratio of CD38+CD138+ plasma cells from 24 newly diagnosed MM patients was (51. 50%±12. 48%) which was significantly higher than CD38+CD138- plasma cells of MM patients (42. 88%±11. 41%)(P=0. 016)and controls 20. 13%±5. 8(P=0. 000). The expression of CD38+CD138+ plasma cells from 24 newly diagnosed MM patients was correlated to the level of malignant plasma cells in there bone marrow(r=0. 546, p=0. 006), serum level of lactate dehydrogenase(LDH)(r=0. 567, p=0. 004), and β2-MG(r=0. 431, p=0. 035). The ratio of Notch1 on the membrane of CD38+CD138+ plasma cells of MM patients was (60. 21%±25. 06%) which was significantly higher than those of CD38+CD138- plasma cells of MM patients 39. 84%±18. 94%(P=0. 000)and controls (38. 34%±19. 39%)(P=0. 004). There was no statistical difference between the two latter groups(P>0. 05). The expression of Notch1 on CD38+CD138+ plasma cells from 24 newly diagnosed MM patients was correlated to the level of malignant plasma cells in there brone marrow(r=0. 914, p=0. 000), serum level of lactate dehydrogenase(LDH) (r=0. 604, p=0. 002), and β2-MG(r=0. 455, p=0. 026). The ratio of Notch1 on the membrane of CD38+CD138+ plasma cells of MM patients who had renal dysfunction was correlated to their abnormal serum creatinine levels. The expression of Notch1 on CD38+CD138+ plasma cells from 17 MM patients who received VD chemotherapy was correlated to the ratio of plasma cell reduction after the first VD chemotherapy(r=0. 842, p=0. 000). The expression of Notch1 mRNA of bone marrow mononuclear from 10 MM patients was (0. 8252±0. 4079) which was significantly higher than those of controls (0. 3759±0. 0813)(p=0. 032). Conclusion: Notch1 over expressed on CD38+CD138+ plasma cells with relation to the effects of early VD therapy and long term outcome of MM. Disclosures: No relevant conflicts of interest to declare.

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CS1: A Potential New Therapeutic Target for the Treatment of Multiple Myeloma.

Blood ◽

10.1182/blood.v108.11.3457.3457 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3457-3457 ◽

Cited By ~ 3

Author(s):

Eric D. Hsi ◽

Roxanne Steinle ◽

Balaji Balasa ◽

Aparna Draksharapu ◽

Benny Shum ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Flow Cytometry ◽

B Cell ◽

Mononuclear Cells ◽

Plasma Cells ◽

Target Cells ◽

Dependent Manner ◽

Myeloma Cells ◽

Effector Cells

Abstract Background: To identify genes upregulated in human memory B and plasma cells, naïve B cell cDNA was subtracted from plasma cell and memory B cell cDNA. One gene that was highly expressed in plasma cells encodes CS1 (CD2 subset 1, CRACC, SLAMF7), a cell surface glycoprotein of the CD2 family. CS1 was originally identified as a natural killer (NK) cell marker. Monoclonal antibodies (mAbs) specific for CS1 were used to validate CS1 as a potential target for the treatment of multiple myeloma (MM). Methods: Anti-CS1 mAbs were generated by immunizing mice with a protein comprising of the extracellular domain of CS1. Two clones, MuLuc63 and MuLuc90, were selected to characterize CS1 protein expression in normal and diseased tissues and blood. Fresh frozen tissue analysis was performed by immunohistochemistry (IHC). Blood and bone marrow analysis was performed using flow cytometry with directly conjugated antibodies. HuLuc63, a novel humanized anti-CS1 mAb (derived from MuLuc63) was used for functional characterization in non-isotopic LDH-based antibody-dependent cellular cytotoxicity (ADCC) assays. Results: IHC analysis showed that anti-CS1 staining occurred only on mononuclear cells within tissues. The majority of the mononuclear cells were identified as tissue plasma cells by co-staining with anti-CD138 antibodies. No anti-CS1 staining was detected on the epithelia, smooth muscle cells or vessels of any normal tissues tested. Strong anti-CS1 staining was also observed on myeloma cells in 9 of 9 plasmacytomas tested. Flow cytometry analysis of whole blood from both normal healthy donors and MM patients showed specific anti-CS1 staining in a subset of leukocytes, consisting primarily of CD3−CD(16+56)+ NK cells, CD3+CD(16+56)+ NKT cells, and CD3+CD8+ T cells. Flow cytometry of MM bone marrow showed a similar leukocyte subset staining pattern, except that strong staining was also observed on the majority of CD138+CD45−/dim to + myeloma cells. No anti-CS1 binding was detected to hematopoietic CD34+CD45+ stem cells. To test if antibodies towards CS1 may have anti-tumor cell activity in vitro, ADCC studies using effector cells (peripheral blood mononuclear cells) from 23 MM patients and L363 MM target cells were performed. The results showed that HuLuc63, a humanized form of MuLuc63, induced significant ADCC in a dose dependent manner. Conclusions: Our study identifies CS1 as an antigen that is uniformly expressed on normal and neoplastic plasma cells at high levels. The novel humanized anti-CS1 mAb, HuLuc63, exhibits significant ADCC using MM patient effector cells. These results demonstrate that HuLuc63 could be a potential new treatment for multiple myeloma. HuLuc63 will be entering a phase I clinical study for multiple myeloma.

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Metabolomics Identifies Potential Biomarkers of Multiple Myeloma Development and Progression

Blood ◽

10.1182/blood.v120.21.3985.3985 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3985-3985

Author(s):

Francesca Fontana ◽

Josè Manuel garcia Manteiga ◽

Magda Marcatti ◽

Francesca Lorentino ◽

Giovanni Tonon ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Plasma Cells ◽

Conflicts Of Interest ◽

In Vitro Tests ◽

Incurable Cancer ◽

Disease Evolution ◽

Cell Counts ◽

Bone Marrow Plasma ◽

Active Disease

Abstract Abstract 3985 Multiple myeloma is a malignancy of plasma cells, which grows at multiple foci in the bone marrow, secretes monoclonal immunoglobulins, and typically induces skeletal destruction, hypercalcemia, anemia, and renal failure. Although it remains an incurable cancer, novel therapeutic regimens have improved overall survival in the last decade. Multiple myeloma originates from post germinal center, terminally differentiated B lymphocytes through a multi-step process involving early and late genetic changes. Multiple myeloma is preceded by monoclonal gammopathy of undetermined significance (MGUS), a frequent age-progressive premalignant expansion of bone marrow plasma cells that behave benignly despite the presence of most myeloma-specific genetic abnormalities. Indeed, development and progression of multiple myeloma are believed to rely on vicious interactions with the bone marrow environment, offering a paradigm to investigate the bone-cancer relationship. In particular, bone and stromal cells are known to be diverted by cancer cells through altered cytokine circuitry. The resulting enhanced osteoclastogenesis and neoangiogenesis, and reduced osteoblast differentiation and activity sustain cancer cell survival, proliferation, migration and chemoresistance. Such crucial interactions, however, have only partially been elucidated in their complexity, dynamics and exact role in disease evolution. A better knowledge of this interplay, still elusive, could help identify prognostic markers, pathomechanisms, and therapeutic targets for future validation. Aiming to achieve an unbiased, comprehensive assessment of the extracellular milieu during multiple myeloma genesis and progression, we performed a metabolomic analysis of patient-derived peripheral and bone marrow plasma by ultra high performance liquid and gas chromatography followed by mass spectrometry. By feature transformation-based multivariate analyses, metabolic profiling of both peripheral and bone marrow plasma successfully discriminated active disease from control conditions (health, MGUS or remission). Moreover, both central and peripheral metabolic scores significantly correlated with bone marrow plasma cell counts. Significant changes in the peripheral metabolome were found to be associated with abnormal renal function in the subset of myeloma patients. Noteworthy, however, renal dysfunction-associated features failed to independently predict disease load, while non-overlapping disease vs. control analyses consistently identified a number of metabolites associated with disease. Among these, increased levels of the C3f-derived peptide, HWESASLL, and loss of circulating lysophosphocholines emerged as hallmarks of active disease. In vitro tests on myeloma cell lines and primary patient-derived cells revealed a previously unsuspected direct trophic role exerted by lysophosphocholines on malignant plasma cells. Altogether, our data demonstrate that metabolomics is a powerful approach suitable for studying the complex interactions of multiple myeloma with the bone marrow environment and general metabolism. This novel strategy holds potential to identify unanticipated markers and pathways involved in development and progression of multiple myeloma. Disclosures: No relevant conflicts of interest to declare.

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Multiple Myeloma Associated GI Polyposis

Blood ◽

10.1182/blood.v120.21.5009.5009 ◽

2012 ◽

Vol 120 (21) ◽

pp. 5009-5009

Author(s):

Nassim Nabbout ◽

Mohamad El Hawari ◽

Thomas K. Schulz

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Plasma Cells ◽

Conflicts Of Interest ◽

Case Reports ◽

Bone Marrow Failure ◽

Bone Lesions ◽

Rare Manifestation ◽

History Of ◽

Central Ulceration

Abstract Abstract 5009 Multiple myeloma is a neoplastic proliferation of monoclonal plasma cells that can result in osteolytic bone lesions, hypercalcemia, renal impairment, bone marrow failure, and the production of monoclonal gammopathy. The gastrointestinal tract is rarely involved in myeloma. GI polyposis is a rare manifestation of extra-medullary disease in multiple myeloma. Such cases usually present as gastrointestinal hemorrhage or intestinal obstruction. A 53-year-old African American male recently diagnosed with multiple myeloma presented with three-day history of rectal bleed and fatigue. EGD showed multiple raised, polypoid, rounded lesions with a superficial central ulceration in the stomach. Colonoscopy showed similar lesions in the ascending and transverse areas of the colon that ranged in size from 5 to 16 mm in diameter. Biopsies showed that these polyps were made of plasma cells. A bone marrow biopsy showed diffuse involvement (greater than 90%) of bone marrow with multiple myeloma with anaplastic features. The patient was started on bortezomib at diagnosis, however, he passed away a few weeks later. This type of metastatic disease has been described in isolated case reports in the literature, while solitary GI plasmacytoma has been reported more frequently. In rare cases, multiple myeloma can involve the GI tract which may lead to bleed or obstruction. This involvement is likely a marker of aggressivity. This example of extra-medullary disease in myeloma is an uncommon variant with features of poor prognosis and dedifferentiation. Disclosures: No relevant conflicts of interest to declare.

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The Frequency of Genetic Anomalies According to Clonal Plasma Cells' Phenotype in Patients with Newly Diagnosed (ND) Multiple Myeloma (MM)

Blood ◽

10.1182/blood.v126.23.5316.5316 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5316-5316

Author(s):

Andrei Garifullin ◽

Irina Martynkevich ◽

Sergei Voloshin ◽

Alexei Kuvshinov ◽

Ludmila Martynenko ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Plasma Cells ◽

Conflicts Of Interest ◽

Risk Group ◽

Risk Groups ◽

Fish Analysis ◽

Newly Diagnosed ◽

Definition Of ◽

Standard Risk

Abstract Background. Genetic anomalies (GA) are primary link of pathogenesis in MM. GA lead to formation of clonal plasma cells, which has different phenotype. Aim. To estimate the incidence of GA and their correlation with clonal plasma cells' phenotype in patients with ND MM. Methods. We analysed 22 patients with ND MM (median age 57 years, range 38-80; male/female - 1:1.75). Cytogenetic analysis was performed on bone marrow samples using standard GTG-method. Metaphase FISH analysis was performed according to the manufacturer's protocol using DNA probes: LSI 13(RB1)13q14, IGH/CCND1, IGH/FGFR3, LSI TP53 (17q13.1). 8-color immunophenotypic by flow cytometry using antibody to CD45, CD38, CD138, CD56, CD19, CD20, CD27 and CD117 antigenes. Results. Translocation t(11;14) was detected in 3/14 (21.4%) patients, del(13q) - 2/14 (14.3%), t(11;14) - 3/14 (21.4%), hypodyploidy - 1/20 (5%), del(17р) - 0% patients. Clonal plasma cells' phenotype CD38+CD138+CD45- was detected in 100%. Expression CD56+ was revealed in 11/22 (50%) patients, CD19+ in 9/22 (40.9%), CD117+ in 5/22 (22.7%), CD20+ in 1/22 (4.5%), CD27+ in 1/22 (4.5%). The frequency of GA didn't depend on clonal plasma cells' phenotype and was 27.3%(3/11) in CD56+ phenotype, 23.8%(5/21) - CD20-, 23.8%(5/21) - CD27-, 23.5%(4/17) - CD117-, 23%(3/13) - CD19-, 22.2%(2/9) - CD19+, 20%(1/5) - CD117+, 18.2%(2/11) - CD56-, 0%(0/1) - CD20+, 0%(0/1) - in CD27+ phenotype. Patients of standard risk group according to mSMART 2.0 with GA had CD19-negative plasma cells' phenotype vs. CD19-positive phenotype in patients of intermediate and high-risk groups (p<0.05). 3-years overall survival in standard risk group with CD19- phenotype was 92,3%, CD19+ - 77,7% (p>0.05). Conclusion . Identification of GA, which has adverse forecast, correlates with CD19+ plasma cells phenotype. The combined definition of plasma cells phenotype and GA can improve the system of risk stratification in MM. Disclosures No relevant conflicts of interest to declare.

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CIC-Mutation As a Potential Molecular Mechanism of Acquired Resistance to Combined BRAF/MEK Inhibition in CNS Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-117203 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3181-3181 ◽

Cited By ~ 2

Author(s):

Matteo Claudio Da Via' ◽

Antonio Giovanni Solimando ◽

Andoni Garitano-Trojaola ◽

Santiago Barrio ◽

Nadine Rodhes ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Exome Sequencing ◽

Plasma Cells ◽

Conflicts Of Interest ◽

Critical Role ◽

Point Mutations ◽

Sequencing Depth ◽

Resistance Development ◽

Average Sequencing Depth

Abstract Central nervous system (CNS) involvement is an extremely rare extramedullary multiple myeloma (MM) manifestation, diagnosed in less than 1% of patients. It is considered an ultimate high-risk feature, associated with unfavorable cytogenetics, and, even with intense treatment applied, survival is short, reaching less than 12 months in most cases. In June 2017 an 81 years old male with a κ light chain MM was referred to our institution for an isolated CNS MM relapse. His cerebrospinal fluid (CSF) demonstrated a high load of clonal plasma cells, however, the patient's bone marrow infiltration was very little with a percentage of plasma cells less than 5%. Imaging, including gold standard MRI and experimental 11C-methionine PET scan, was performed, and high metabolic activity was detected supra- and infratentorially as well as in the right femur and the clivus. Following CD138+ cell purification we analyzed the specimen with M3P (v3.0) a disease specific in-house customized, next generation targeted sequencing panel for MM (Ion torrent platform). This includes most commonly mutated MM genes, actionable drug targets and drug resistance associated genes. The average sequencing depth increased 700X and spatial MM heterogeneity was detected, as the CFS cells harbored a clonal BRAFV600E mutation, absent in the bone marrow. Initial intrathecal and systemic chemotherapy with Cytarabine and Thiotepa was intolerable, thus the patient underwent a combined target inhibition with Dabrafenib/Trametinib, well known specific BRAF and a MEK 1/2 inhibitors. The patient displayed a rapid complete response (Figure. 1A), however, disease relapse occurred after three months of therapy. We obtained a sequential CFS sample and Whole Exome Sequencing (Illumina platform) was applied to pre and post therapy CFS sampling. Exome sequencing of the two time points performed an average sequencing depth of 115X; a total number of 97 non-silent coding variants (missense, nonsense, indels, splice) with an allele frequency higher than 5% were detected. In detail, 19 point mutations were acquired at relapse, including a subclonal missense mutation in CIC (p.A984P, VRF 17%), recently identified as a candidate gene contributing to MEK/BRAF resistance development. Next, we established a CIC knock-down model electroporating a specific anti-CIC siRNA into U266 MM cell line. We cultured the silenced and not-silenced cells with Trametinib and Dabrafenib, either as single agents, or in combination. As expected, we observed resistance induction to the combination of the two drugs (Row Factor 85.94%; P<0.0001, Two-way ANOVA) suggesting a critical role for this patient derived mutation for his MEK/BRAF resistance development (Figure 1C, D). In order to better clarify the landscape pathway related to CIC we analyzed expression data from 647 patients enrolled in the MMRF CoMMpass trial. Remarkably, we found a significant down-regulation of ERF and ETV6 (t-test -9.95, -9.93, P <0.001, respectively), two well characterized tumor suppressor genes correlated with the re-activation of the RAS downstream pathway (Figure 1B). This is the first report giving evidence for a potential role of point mutations in CIC as a resistance mechanism to targeted MEK/BRAF inhibition in BRAF mutated MM. The performed pathway analysis significantly extends the insights of the resistance mechanisms highlighted. Our results foster a statistically powered study to corroborate the clinical relevance. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

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Multiple Myeloma - Atypical Presentation - Clinicopathological Correlation

Journal of Evolution of Medical and Dental Sciences ◽

10.14260/jemds/2021/715 ◽

2021 ◽

Vol 10 (40) ◽

pp. 3526-3532

Author(s):

Emani Usha Bhargavi ◽

Vaddadi Suresh

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Plasma Cells ◽

Wide Spectrum ◽

Case Series ◽

Malignant Neoplasm ◽

Routine Practice ◽

Cutaneous Lesions ◽

Clinical Presentations ◽

Case Series Study

BACKGROUND Multiple myeloma, malignant neoplasm of plasma cells producing monoclonal para protein is one of the most common haematological malignancies we see in our routine practice. Multiple myeloma has varied and diverse clinical presentations, of which most common clinical features will be anaemia, bone pain, fever, fatigue, weight loss, paraesthesia, renal failure, pathological fractures, cutaneous lesions, etc. We hereby, present a series of multiple myeloma cases with unusual presentation over a period of 3 years. The purpose of the study was to evaluate the unusual and rare clinicohaematological presentation in patients with multiple myeloma. METHODS In this case series study, we reviewed bone marrow aspirate & / or biopsy slides in our hospital from January 2017 to January 2020. Patients diagnosed with multiple myeloma were selected. Patients’ clinical information, haematological and other findings were obtained from the medical records department and compiled, and correlation was done. RESULTS We came across a total of 9 cases of multiple myeloma with very unusual and rare clinical presentations. A thorough clinical, radiological, haematological, biochemical and histopathological correlation was done before giving a final diagnosis in these cases. Rare cutaneous and other involvement of multiple myeloma was noted. CONCLUSIONS Multiple myeloma is the most common malignancy with comparatively poor prognosis. However, early diagnosis of multiple myeloma always helps the clinician in improving the outcome and has been shown to have better prognosis. The present case series is an attempt to understand the clinico-pathological correlation, wide spectrum of clinical presentation and associated rarity of presentations. KEY WORDS Myeloma; Lytic Lesions; Bone Marrow

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'Role of bone marrow stromal cells in the growth of human multiple myeloma

Blood ◽

10.1182/blood.v77.12.2688.bloodjournal77122688 ◽

1991 ◽

Vol 77 (12) ◽

pp. 2688-2693 ◽

Cited By ~ 3

Author(s):

F Caligaris-Cappio ◽

L Bergui ◽

MG Gregoretti ◽

G Gaidano ◽

M Gaboli ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

B Lymphocytes ◽

Stromal Cells ◽

Mononuclear Cells ◽

Plasma Cells ◽

Critical Role ◽

Peripheral Blood Mononuclear ◽

Human Multiple Myeloma

We have verified the hypothesis that multiple myeloma (MM) may be disseminated by circulating clonogenic cells that selectively home to the bone marrow (BM) to receive the signal(s) leading to proliferation, terminal differentiation, and production of the osteoclast activating factors. Long-term cultures of stromal cells have been developed from the BM of nine patients with MM. These cells were mostly fibroblast- like elements, interspersed with a proportion of scattered macrophages and rare osteoclasts. BM stromal cells were CD54+, produced high levels of interleukin-6 (IL-6) and measurable amounts of IL-1 beta, and were used as feeder layers for autologous peripheral blood mononuclear cells (PBMC). After 3 weeks of cocultures, monoclonal B lymphocytes and plasma cells, derived from PBMC, developed and the number of osteoclasts significantly increased. Both populations grew tightly adherent to the stromal cell layer and their expansion was matched by a sharp increase of IL-6 and by the appearance of IL-3 in the culture supernatant. These data attribute to BM stromal cells a critical role in supporting the growth of B lymphocytes, plasma cells, and osteoclasts and the in vivo dissemination of MM.

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High Dimensional Immune Profiling in Smoldering Multiple Myeloma Identifies Novel Organizing Features of the Tumor Microenvironment

Blood ◽

10.1182/blood-2019-130554 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4384-4384

Author(s):

Hearn Jay Cho ◽

Deepak Perumal ◽

Adeeb H Rahman ◽

Seunghee Kim-Schultze ◽

Jennifer Yesil ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Tumor Microenvironment ◽

Tumor Cells ◽

Research Funding ◽

Mononuclear Cells ◽

Plasma Cells ◽

High Dimensional ◽

Integrated Analysis ◽

Symptomatic Disease

Multiple myeloma (MM) is a malignancy of plasma cells that arises from premalignant Monoclonal Gammopathy of Undetermined Significance (MGUS) and often progresses through an asymptomatic Smoldering (SMM) phase lasting months or years before manifesting clinical symptoms warranting therapy. Current research indicates that the tumor microenvironment (TME) in the bone marrow may play a significant role in governing progression to symptomatic disease. Therefore, understanding of the interactions between malignant plasma cells and the TME in early disease states is critical in the pursuit of therapies that will prevent progression to symptomatic disease. We performed high dimensional genomic and immunologic analysis of bone marrow specimens from 73 subjects with SMM. We performed RNA-seq on the malignant plasma cells isolated by anti-CD138 magnetic bead positive selection, mass cytometry (CyTOF) and T cell receptor sequencing (TCR Seq) of CD138-depleted bone marrow mononuclear cells, and proteomics, seromic, and grand serology analysis of bone marrow plasma. These samples and assays provided a broad view of the tumor cells and the cellular and soluble components of the TME. Each of these assays identified self-organizing clusters of subjects, indicating that subgroups of SMM patients shared common characteristics in the tumor or TME populations. We then applied novel bioinformatic methods to compare data from pairs, trios, quartets, and quintets of assays to identify communities of subjects with similar immunologic and genomic characteristics. Integrated analysis of CyTOF, proteomic, and TCR Seq resolved three distinct communities with a high degree of significance. These communities shared distinct cellular and proteomic features that suggested early adaptive, activated adaptive, or innate immune characteristics. These results suggest that the continuum from MGUS to MM does not consist of a single pathway in either the tumor cells or the TME, and that complex interactions ultimately determine progression. This suite of assays (CyTOF, proteomics, and TCR Seq) may be applicable in translational and clinical studies to understand key tumor and immune determinants of SMM and lead to rationally designed therapy to replicate these conditions to prevent progression to symptomatic disease. Disclosures Cho: Genentech: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; The Multiple Myeloma Research Foundation: Employment; Takeda: Research Funding; BMS: Consultancy; Agenus: Research Funding; GSK: Consultancy. Adams:Janssen Pharmaceuticals R&D: Employment, Other: Own Stock. Parekh:Foundation Medicine Inc.: Consultancy; Celgene Corporation: Research Funding; Karyopharm Inc.: Research Funding.

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